Lumasiran in the Management of Patients with Primary Hyperoxaluria Type 1: From Bench to Bedside

Abstract

Primary hyperoxaluria (PH) is a rare genetic disease caused by excessive hepatic production and elevated urinary excretion of oxalate that leads to recurrent nephrolithiasis, nephrocalcinosis and, eventually, kidney failure. As glomerular filtration rate declines, oxalate accumulates leading to systemic oxalosis, a debilitating condition with high morbidity and mortality. Although PH is usually diagnosed during infancy, it can present at any age with different phenotypes, ranging from mild symptoms to extremely debilitating manifestations. PH is an autosomal recessive disorder and, to date, three types have been identified: PH1, PH2 and PH3. PH1 is the most common and most aggressive type, accounting for almost 80% of primary hyperoxaluria diagnoses. Until 2020, general treatment for PH1 consisted mainly in high fluid intake, urine alkalization, surgical management of recurrent nephrolithiasis and eventually, if and when kidney failure occurred, intensive dialysis regimens and transplantation strategies (simultaneous or sequential liver-kidney transplant or isolated liver/kidney transplant in carefully selected patients). Specific treatment did and still consists in administration of pyridoxine hydrochloride, although it is only effective in a subset of PH1 patients. Lumasiran, a novel biological drug based on mRNA interference that has been recently approved in the US and European Union, showed promising results and is set to be a turning point in the management of PH1. This literature review aims to summarize the available evidence on PH1 treatment with lumasiran, in order to provide both pediatric and adult nephrologists and clinicians with the knowledge for the identification and management of PH1 patients suitable for treatment.

Lumasiran for primary hyperoxaluria type 1: What we have learned?

“…Lumasiran is a synthetic double-stranded small interfering RNA (siRNA) covalently conjugated with the N-acetylgalactosamine (GalNAc) ( 30 , 31 ). Its ligand, GalNAc, a carbohydrate with high affinity for asialoglycoprotein receptor (ASGPR), which has a targeting effect, trigger endocytosis by binding to ASGPR, that delivering the siRNA preferentially targeted to the liver cytoplasm and adding into the RNA-induced silencing complex ( 30 ).…”

“…According to pharmacokinetic studies, lumasiran exhibited linear to slightly nonlinear, time-dependent activity in plasma ( 9 ). The average time to reach a maximum plasma concentration is 4 h after administration, the plasma protein binding can exhibit moderate to high (77%–85%), and it can be detected up to 24–48 h post dose ( 9 , 30 , 31 ). The average terminal plasma half-life is 5.2 h, the apparent central volume of distribution in adults is 4.9 L, and the plasma clearance is 26.5 L/h ( 9 , 30 , 31 ).…”

“…The average time to reach a maximum plasma concentration is 4 h after administration, the plasma protein binding can exhibit moderate to high (77%–85%), and it can be detected up to 24–48 h post dose ( 9 , 30 , 31 ). The average terminal plasma half-life is 5.2 h, the apparent central volume of distribution in adults is 4.9 L, and the plasma clearance is 26.5 L/h ( 9 , 30 , 31 ). Urinary clearance in both adults and children ranged from 2.0 to 3.4 L/h, with urinary excretion accounting for 7%–26% of the dose administered ( 9 , 30 , 31 ).…”

“…The average terminal plasma half-life is 5.2 h, the apparent central volume of distribution in adults is 4.9 L, and the plasma clearance is 26.5 L/h ( 9 , 30 , 31 ). Urinary clearance in both adults and children ranged from 2.0 to 3.4 L/h, with urinary excretion accounting for 7%–26% of the dose administered ( 9 , 30 , 31 ). Because lumasiran has a long half-life in liver and its pharmacokinetic characteristics in plasma, its administration frequency of once monthly or quarterly can still maintain the pharmacodynamic effect of the drug within the dosing interval without drug accumulation in plasma ( 9 , 30 ).…”

Clinical and molecular characterization of primary hyperoxaluria in Egypt

“…Furthermore, age at presentation of PH1 is variable with heterogeneous clinical presentation varying from severe infantile onset with failure to thrive and renal impairment down to solitary or multiple stones in adult patients and could be even asymptomatic 11 . The discovery of the mRNA interfering drug lumasiran and its recent approval in the USA and EU as the first specific therapy for PH1 has given the early detection and genetic confirmation of PH1 patients much more importance 12 .…”